Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate ...immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.
We study the physical conditions, elemental abundances, and kinematics of the high-velocity clouds (HVCs) along the sight lines toward active galaxies HE 0226-4110 and PG 0953+414 using Hubble Space ...Telescope Space Telescope Imaging Spectrograph and Far Ultraviolet Spectroscopic Explorer data. No 21 cm H I emission is detected in these clouds, but our observations reveal multiple components of HVC absorption in lines of H I, C II, C III, C IV, O VI, Si II, Si III, and Si IV in both directions. We investigate whether photoionization by the extragalactic background radiation or by escaping Milky Way radiation can explain the observed ionization pattern. We find that photoionization is a good explanation for the C II, C III, Si II, and Si III features but not for the O VI or C IV associated with the HVCs, suggesting that two principal phases exist: a warm (T - 10 super(4) K), photoionized phase and a hotter (T = 1-3 x 10 super(5) K), collisionally ionized phase; the broader line widths of the high ions are consistent with this multiphase hypothesis. The warm HVCs toward HE 0226-4110 have high levels of ionization (97%-99%) and metallicities (Z/H between -0.9 and -0.4) close to those in the Magellanic Stream, which lies 11 away on the sky at similar velocities. These HVCs may well be stripped fragments of the Stream that have been ionized by the pervading radiation field; they have thermal pressures that would place them close to equilibrium in a fully ionized 10 super(6) K Galactic corona with n sub(H) = 4-9 x 10 super(-5) cm super(-3) at 50 kpc. The warm HVCs seen at -146 and 125 km s super(-1) toward PG 0953+414 have Z/H = -0.6 c 0.2 and -0.8 c 0.2, respectively, suggesting they are not formed from purely Galactic material. A minisurvey of the hot, collisionally ionized HVC components seen here and in five other sight lines finds that in 11/12 cases, the high ions have kinematics and ionic ratios that are consistent with an origin in conductive interfaces, where energy flows into the HVCs from a hot surrounding medium and produces O VI- and C IV-bearing boundary layers. However, the broad absorption wing on the O VI profile toward PG 0953+414 is not completely explained by the interface scenario. This feature may be tracing the outflow of hot gas into the Milky Way halo as part of a Galactic fountain or wind.
This paper applies and evaluates an automatic mutual information-based registration algorithm across a broad spectrum of multimodal volume data sets. The algorithm requires little or no ...pre-processing, minimal user input and easily implements either affine, i.e. linear or thin-plate spline (TPS) warped registrations. We have evaluated the algorithm in phantom studies as well as in selected cases where few other algorithms could perform as well, if at all, to demonstrate the value of this new method. Pairs of multimodal gray-scale volume data sets were registered by iteratively changing registration parameters to maximize mutual information. Quantitative registration errors were assessed in registrations of a thorax phantom using PET/CT and in the National Library of Medicine's Visible Male using MRI T2-/T1-weighted acquisitions. Registrations of diverse clinical data sets were demonstrated including rotate—translate mapping of PET/MRI brain scans with significant missing data, full affine mapping of thoracic PET/CT and rotate—translate mapping of abdominal SPECT/CT. A five-point thin-plate spline (TPS) warped registration of thoracic PET/CT is also demonstrated. The registration algorithm converged in times ranging between 3.5 and 31 min for affine clinical registrations and 57 min for TPS warping. Mean error vector lengths for rotate—translate registrations were measured to be subvoxel in phantoms. More importantly the rotate—translate algorithm performs well even with missing data. The demonstrated clinical fusions are qualitatively excellent at all levels. We conclude that such automatic, rapid, robust algorithms significantly increase the likelihood that multimodality registrations will be routinely used to aid clinical diagnoses and post-therapeutic assessment in the near future.
Although numerous characteristics impact faculty research productivity, and although researchers have suggested comprehensive theoretical models to explain the relationship between these ...characteristics and levels of faculty research productivity, few studies have assessed these models. This study tests the ability of the Bland et al. (2002) model-based on individual, institutional, and leadership variables influencing faculty research productivity-to explain individual and group (department) research productivity within the context of a large medical school.
This study used data from a University of Minnesota Medical School-Twin Cities vitality survey conducted in 2000 that had a response rate of 76% (n = 465 faculty). A statistical software package was used to conduct t tests, logistic regressions, and multiple regressions on these data.
The validity of faculty, department, and leadership characteristics identified in the Bland et al. (2002) model were confirmed as necessary for high levels of research productivity. Faculty productivity was influenced more by individual and institutional characteristics; group productivity was more affected by institutional and leadership characteristics.
The characteristics and groupings (individual, institutional, and leadership) in the Bland et al. (2002) model predict faculty research productivity. Research productivity is influenced by the interaction of the three broad groupings, and it is the dynamic interplay of individual and institutional characteristics, supplemented with effective leadership, that determines the productivity of individuals and departments.
This paper presents a study of the production of a single $W$ boson in association with one or more jets in proton-antiproton collisions at $\sqrt{s}=1.96$ TeV, using the entire data set collected in ...2001-2011 by the Collider Detector at Fermilab at the Tevatron, which corresponds to an integrated luminosity of $9.0$ fb$^{-1}$. The $W$ boson is identified through its leptonic decays into electron and muon. The production cross sections are measured for each leptonic decay mode and combined after testing that the ratio of the $W(\rightarrow \mu\nu)+$jets cross section to the $W(\rightarrow e\nu)+$jets cross section agrees with the hypothesis of $e$-$\mu$ lepton universality. The combination of measured cross sections, differential in the inclusive jet multiplicity ($W+\geqslant N$ jets with $N=1,\,2,\,3, \textrm{or }4$) and in the transverse energy of the leading jet, are compared with theoretical predictions.
A measurement of the inclusive production cross section of isolated prompt photons in proton-antiproton collisions at center-of-mass energy s=1.96 TeV is presented. The results are obtained using ...the full Run II data sample collected with the Collider Detector at the Fermilab Tevatron, which corresponds to an integrated luminosity of 9.5 fb−1. The cross section is measured as a function of photon transverse energy, ETγ, in the range 30<ETγ<500 GeV and in the pseudorapidity region |ηγ|<1.0. The results are compared with predictions from parton-shower Monte Carlo models at leading order in QCD and from next-to-leading-order perturbative QCD calculations. The latter show good agreement with the measured cross section.
The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown ...that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.
A measurement of the inclusive production cross section of isolated prompt photons in proton-antiproton collisions at center-of-mass energy $ \sqrt{s}=1.96 $ TeV is presented. The results are ...obtained using the full Run II data sample collected with the Collider Detector at the Fermilab Tevatron, which corresponds to an integrated luminosity of 9.5 fb-1. The cross section is measured as a function of photon transverse energy, E γ T , in the range 30 < E γ T <500 GeV and in the pseudorapidity region |ηγ|<1.0. The results are compared with predictions from parton-shower Monte Carlo models at leading order in QCD and from next-to-leading-order perturbative QCD calculations. The latter show good agreement with the measured cross section.
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